AMPK activator decelerates osteoarthritis development by inhibition of β-catenin signaling in chondrocytes

Zhenglin Zhu; Yanran Huang; Jun Li; Dan Yi; Junyi Liao; Jun Xiao; Guozhi Xiao; Liping Tong; Wei Huang; Chen Di

doi:10.1016/j.jot.2022.10.005

AMPK activator decelerates osteoarthritis development by inhibition of β-catenin signaling in chondrocytes

J Orthop Translat. 2022 Nov 14:38:158-166. doi: 10.1016/j.jot.2022.10.005. eCollection 2023 Jan.

Authors

Zhenglin Zhu^{1

2

3}, Yanran Huang^{1

2

3}, Jun Li⁴, Dan Yi^{1

2}, Junyi Liao³, Jun Xiao⁵, Guozhi Xiao⁶, Liping Tong¹, Wei Huang³, Chen Di^{1

2}

Affiliations

¹ Research Center for Computer-Aided Drug Discovery, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
² Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
³ Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
⁴ Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, USA.
⁵ Department of Orthopaedics, NanFang Hospital, Southern Medical University, Guangzhou, 510515, China.
⁶ School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China.

Abstract

Background: Osteoarthritis (OA) is a common degenerative joint disease with significant negative impact on the quality of life. It has been reported that abnormal upregulation of β-catenin signaling could lead to OA development; however, the upstream regulatory mechanisms of β-catenin signaling have not been determined.

Methods: Primary rat chondrocytes and ATDC5 chondrocyte cell line were stimulated with AKT2 and treated with or without metformin, an adenosine 5'-monophosphate-activated protein kinase (AMPK) activator. Westerrn blot analysis, luciferase reporter assay and immunofluorescent (IF) staining were performed to examine changes in β-catenin^S552 phosphorylation and β-catenin nuclear translocation in ATDC5 cells and in primary chondrocytes.

Results: We found that metformin inhibited β-catenin^S552 phosphorylation in ATDC5 cells and in primary chondrocytes in a time-dependent manner. Metformin inhibited β-catenin nuclear translocation and β-catenin reporter activity. In addition, metformin also attenuated the expression of β-catenin downstream target genes. We also demonstrated that metformin inhibited β-catenin^S552 phosphorylation in articular cartilage in mice.

Conclusion: These findings suggest that metformin may exert its chondro-protective effect at least in part through the inhibition of β-catenin signaling in chondrocytes.

The translational potential of this article: This study demonstrated the interaction between AMPK and β-catenin signaling in chondrocytes and defined novel molecular targets for the treatment of OA disease.

Keywords: AMPK; Chondrocyte; Metformin; Osteoarthritis; Osteoarthritis, OA; Phosphorylation; β-catenin.